Process for the preparation of 3-oxo-delta4-6-methyl steroids



United States Patent This invention relates to organic compounds and has particular reference to a process for the preparation of 3- oxo-n -6 methyl steroids. i

It is an object of the present invention to provide a new and improved process for the preparation of the therapeutically valuable 6a-methyl steroidal hormones of the androstane and pregnane series which are now well-known in clinical practice. According to the present invention there is provided process for the preparation of a 3-oxo-A 6-methyl steroid which process comprises treating a corresponding 6-substituted steroidal-3,5-diene including the formula CHR where R is O-alkyl, O-hydroxyalkyl, 'O-cycloalkyl or alkaryl and R is H =0, or

OH OAcyl with an acidified metallic catalyst in the presence of at least one equivalent with respect to the steroid of a hydrogen donor in an organicsolvent.

Palladium charcoal is the preferred metallic catalyst.

Slight acidity of the catalyst is an essential feature of the present invention. Palladium charcoal as obtained from commercial sources is found by us to be sufficiently acidic in most cases to be satisfactory forgthe purpose of the invent-ion. Should the catalyst be insuificiently acidic for the vpurpose of the invention, which will be apparent by the sluggislmess of the reduction process, then it may be rendered suitable by addition of an acid .s uch'for example as acetic acid. The addition of acids such as acetic acid may in any event be advantageous in certain cases, such for example, as withill-oxo compounds Palladium on barium'sulphate, when acidified with a small. quantity of' an acid' such for example as acetic acid, may also, be employed but is'less effective than palladiuin charcoal, whilst platinum/carbon, ru-

thenium/ carbon and rhodium/ carbon are less satisfactory asthe rate of reduction production scale.

with them is too slow on a Ethanol is the preferred organic solvent, but. other hydroxylic solvents such as methanol and propanol, the lower ethers of ethylene glycol, pand s-butanol may also be employed. i I cyclohexene is the preferred hydrogen donor. Other hydrogen donors which may be employed include such unsaturated hydrocarbons as cyclohexadiene, phellandrene, tetralin, benzyl alcohol and chemical equivalents thereof. i

Conversion of." compounds of Formula I into the 6- methyl products-may lead- 10600- 6,8- or a mixture of 6m and 6 8-methyl.derivatives. In general, the 6a-methyl derivative admixed with smaller quantities of'the 6,8-

ethyl isomer will be obtained although in certain cases h ICC the f ipmethyl isomer may beformed in predominant;

amount. Conversion of the 6fl-methyl isomer into the more stable 6a-methyl form may be readily achieved .by methods of prior art such for example as treatment in ethanolic solution with catalytic quantities of hydrochloric acid or potassium hydroxide, conversion into the enamine or 3-enol ether and subsequent regeneration. 1

In the preferred embodiment of the invention to part of the 3,5-dienic steroidal starting material in 10 to 20 vols. of ethanol is added 0.2 to.1 partv palladium charcoal and 1 to -5 parts cyclohexene and the mixture heated under reflux for 1 to 3 hours. 'If desired, the

requisite time of heating may be determined in a particular instance by removing an aliquot of the reaction solution, filtering to remove catalyst, and examining the resulting filtrate by UV. or LR; techniques. "The time.

of reduction should not be prolonged unnecessarily 'as the resulting. 6-methyI-3-oxo-A steroid hydrogenation product can undergo slow reduction under the experimental conditions which .form'the process of the invention.

The starting materials are described in our copending application No. 150,140, filed November 6, 1961, now US. Pat. No. 3,114,750.- For their preparation the 3-enol ether of a 3-oxo-A steroid is treated e.g. with phosgene/dimethylformarnide.

present 7 in methylene dichloride at 0 C. and the resulting mixture poured into aqueous sodium acetate when the 6-formyl steroid (I; R=O) is obtained. Reduction of the 6- formylsteroid (I; R '=O) with, for example, a borohydride, furnishes the corresponding 6-hydroxymethyl steroid (application No. 150,176, filed November 6 1961,.now US. Patent No. 3,095,411). The starting materials are prepared from the foregoing 6-hydroxymetliyl steby cautious acylation in pyridine'solution at room temperature, after which the Inixtureqmay be poured into cold wateror brine and the precipitated products-isolated by filtration. Such acylated materials are, in general, sufliciently pure for direct conversion into -methylate d- 3-oxo-A -steroids. If desired, they may be purified by careful recrystallisation from neutral organic solvents preferably in the presence of a basic additive" such as pyridine. f l j.

The process of the invention is generally applicable to 6-formyl, 6-hydroxymethyl-and, 6-acyloxymethyl steroids which may belong to the androsta'ne, 19-norandrostan'e, 9fi,10u-androstane,. pregnane, 19-norpregnane, 9/3,10a-pregnane, chclestane, stigma'stane, ergostane or spirostane series. Such ring systems may additionally be substituted by the common func'tional groupsencountered in steroidal chemistry including hydroxy methyl), 14,15, 17, 18, 19, 20 and 21 (includ ing the condensation products of 16a, 17a-glycols with carbonyl components).

Carbonyl groups such for example as carbonyl groups at 11,12,15,16,17,18 and 20.

Carbalkoxy groups at C C C17 or in the sidechain.

Alkyl groups, in particular Me groups at C C C C C and ethyl at C Alkenyl in particular vinyl and allyl at C Methylene and ethylidene groups at C C and C groups such as benzylidene at C Lactone, ether and spiroketal residues: Spirol-actone residues such as O.CO.CH .CH attached to C etheric groups at C and bridging C and C spiroketal moieties such as are present in diosgenone, 20,20-ethylenedioxy groups, 17,17-ethylenedioxy groups and similar functional derivatives.

Halogen groups and in particular fluorine at C and C Unsaturated linkages in particular at C C C C and C17(20).

Ketol groups in particular acylated ketol groups at G -C ir- 20 and an-21- Cortical side chains, both acylated, or converted into such protective" derivatives as bismethylenedioxy, cycliccarbonates, cyclic acetonides or orthoformates.

Epoxides particularly at C The process of the invention may be applied to the 3- enol ethers of 6-formyl, 6-hydroxymethyl and 6-acyloxymethyl derivatives of the following steroids and acyl derivatives thereof.

Testosterone 2 -methyltestosterone 17u-methyltestost erone 9 1 1)-dehydro-17a-methyltest0ster0ne 17a-acyloxyprogesterone 9 1 1)-dehydro-17a acyloxyprogesterone 16-methyl-17a-acyloxyprogesterone 9 1 1 -dehydro-l 6-methyl- 17a-acyloxyprogesterone l6-methylenel7a-acyloxyprogesterone 9 1 1)-dehydro-16-methylene-17a-acyloxyprogesterone 17a-acyloxy-16-ethylideneprogesterone 16a, l7a-dimethylmethylenedioxyprogesterone 9 1 l -dehydrol 6a,17a-dirnethylmethylenedioxyprogesterone Cortisone 16-methylcortisone 2 l-methylcortisone l-methylenecortisone 16a-hydroxy cortisone and the (1611,17 a -acetonide thereof Hydrocortisone 16-methylhydrocortisone 21-methylhydrocortisone 16-methylenehydrocortisone V 16a-hydroxyhydrocortisone and the (16a,17a)-acetonide thereof 17a,2 1-dihydroxypregna-4,9 (1 l -diene-3,20-dione 16-methyl-17a,21-dihydroxypregna-4,9(1 l -diene- 3,20-dione 21-methyl-17a,21-dihydroxypregna-4,9(11)-diene- 3,20-dione 1 16-methylene- 17 a,2 1 -dihydroxypregna-4,9 1 1 -diene- 3 ,20-dione 1fia-hydroxy-17a,21-dihydroxypregna-4,9(11 )-diene- 3,20-dione and the (16,17)-acetonide thereof 2 l-fiuoro-17a-hydroxypregna-4,9(11)-diene-3,20-dione and the 16,17 -acetonide thereof 2 l-fluoro-l7a-hydroxypregn-4-ene-3 ,1 l ,20-tri0ne and the (16,17)-acetonide thereof 21-fiuoro-1 1, 17a-dihydroxypregn-4-ene-3 ,20-dione and the 1 6-17 -acetonide thereof 21-hydroxypregna-4,17-dien-3-one 1 1 oxo-21-hydroxypregna-4,17-dien-3-one 11,2 l-dihydroxypregna-4,l7-dien-3-one 9(11)-dehydr0-21-hydroxypregna-4,l7-dien-3-one The 9oc-fill01p derivatives of the above llfi-hydroxy and ll-oxo-steroids.

Following is a description by way of example of methods of carrying the invention into effect.

Example 1 A mixture of 17B-acetoxy-6-hydroxymethyl-3-cthoxyandrosta-3,S-diene (0.5 g.), ethanol (10 ml.), cyclohexene (2 ml.) and 5% palladium on charcoal (0.15 g.)

lated as in Example 1, was purified by crystallisation from was stirred and heated under reflux for 2 /2 hours. The catalyst was removed by filtration and the clear solution was poured into water. The solid thus obtained was recrystallised from aqueous methanol to give 6u-methyltestosterone acetate, M.P. to 141 C., identical with an authentic specimen.

Example 2 A mixture of l7a-acetoxy-6-acetoxymethyl-3-methoxypregna-3,5-dien-20-one (1 g.) [obtained as a gum by treatment of 17a-acetoxy-6-hydroxymethyl 3-methoxypregna-3,5- dien-'20-one with acetic anhydride and pyridine (1:5) for 2 hours at room temperature], 5% palladium on charcoal (0.3 g), ethanol (25 ml.) and cyclohexene (2 ml.) was stirred and heated under reflux for 1 /2 hours. The product, isolated as in Example 1, was purified from aqueous acetone. It had M.P. 206 to 209 C., and was identical with authentic 17a-acetoxy-6amethylprogesterone.

Example 3 The Vilsmeier reagent was prepared at 0 C. from dimethylformamide (25 ml.) in anhydrous methylene chloride (50 ml.) and phosgene (16 g.) in methylene chloride ml.). Cortisone acetate-3-enol methyl ether (Ercoli and Jardi, J. Amer. Chem. Soc., 1960,- 82 746) (25 g.) in'methylene chloride (250 ml.) containing pyridine (0.5 ml.) was added and the mixture stirred for 2 hours, when an organge-red precipitate separated. Sodium acetate (30 g.) in water (100 ml.) and methanol (100 ml.) was addedand the mixture stirred for 20 minutes then diluted with water and ether (600 ml.). The organic layer was washed with water until the washings were colourless, dried (Na SO stirred with decolourising charcoal, filtered, and the solvents were removed under reduced pressure. The product, purified from aqueous methanol, was 2l-acetoxy-6-formyl l7a-hydroxy- 3-methoxypregna-3,S-diene-l1,20-dione, flakes M.P. 200 to 204 C., [oa] -15 (c., 0.97 chloroform), A .218 (e=10,890) and 322 mu (e=14, 980).

A mixture of 21-acetoxy-6-formyl 17 c-hydroxy-3- methoxypregna-3,S-diene-l1,20dione (0.5 g.) ethanol (20 ml.), acetic acid (10 ml.) cyclohexene (5 ml.) and 5% palladium on barium sulphate (0.5 g.) was stirred i and heated under reflux for 3 hours. The product, iso- 2-ethoxy ethanol. it had 240 to 242 C., and was identical with authenic 6u-methyl cortisone acetate;

: Example 4 A mixture of 21-acetoxy-6-forrnyl-3 -methoxypregna- 3,5-dien-20-one (1 g.), 5% palladium on charcoal (0.25 g.), cyclohexene (5 ml.), acetic acid (5 ml.) and ethanol (25 ml.) was heated under reflux for 3 hours. The product, isolated as in Example 4, was crystallised from aqueous methanol to give 21-acetoxy-6a-methylpregn-4- ene-3,20-dione as needles, M.P. 128 to 130 C., identical with an authentic specimen.

Example 6 A mixture of 3-ethoxy-6-formyl-l6u,l7a-isopropylidenedioxypregna-3,5-dien-20-one (1.5 g.), 5% palladium on charcoal (0.4 g.), cyclohexene 10 ml.) and ethanol (75 ml.) was heated under reflux for 2 /2 hours. The product, isolated as in Example 1, crystallised from aqueous methanol to give 6a-methyl-l6a,l7a-isopropylidenedioxypregnl-ene-3,20-dione as leaflets, M.P. 166 to 167 C., identical with an authentic specimen.

Example 7 'A mixture of 6-formyl-3-methoxypregna-3,5-dien-20- one (0.5 g.), 5% palladium on charcoal (0.15 g.), cyclohexene (1 ml.) and ethanol. was heated under reflux for V 2 hours. The. product, isolated as in Example 4, crystallised from aqueous methanol to give 6a-methylpregn-4- ene-3,20-dione' as needles, M.P. 122 to 123 C., identical with an authentic specimen.

Example 8 A mixture of 6-formyl-3-methoxyandrosta-3,5-dien-17- one (1 g.), 5% palladium onbarium sulphate (0.4 g.), cyclohexene. (2 ml.), acetic acid (10 ml.) and ethanol (20 ml.) 'was heated under reflux for 3 /2 hours. The product, isolated as in Example 4, was crystallised from acetone/hexane to give 6a-methylandrost-4-ene-3,17- dione as needles M.P. 167 to 168 C., identical with an authentic specimen.

Example 9 V A mixture of 17li-acetoxy-3-ethoxy-6-formyl-2a-methylandrosta-3,5-diene (0.5 g.), 5% palladium'on charcoal (0.15 g.), cyclohexene (1 ml.) and ethanol (10 ml.) was heated under reflux for 2 hours. The product,isolated as in Example 4, crystallised from aqueous acetone to give 17,8-acetoxy 2a,6a dimethylandrostl-en-Z -ne as rods, M.P. 134 to 136 C., identical with an authentic specimen.

Example 10 A mixture of 17e-acetoxy-6-hydroxymethyl-3-methoxy- 1 6 methylenepregna-3',5adien-20-one (0.5 .g.), palladiurn on charcoal (0.15 g.), cyclohexene 1(2 .1111.) and ethanol ml.) was heated underreflux for 3 hours. The product, isolated as in Example 1, was crystallised from methanol to give'l7a acetoxy 6u-methyl-l6-methylenepregn-4-en-3,20-dione as needles M.P. 208 to 210 5C., identical with an authentic specimen.

: A r'nixture of ethyl '3-ethoxy 6-forinylprgna-35,17 (20)"-trien-21-oate (1 g.), 5% palladiumon charcoal Example 1 (0.3 g.), benzyl alcohol (2 ml.) and ethanol ml.) was heated under reflux for 3 hours. The product, isolated as in Example 4, was crystallised from ethanol to give ethyl 6a-methyl-3-oxopregna-4,17(20)-dien-21-oate as needles, M.P. 158 C., identical with an authentic specimen.

Example 12 A mixture of 6-formyl-3-methoxy-16x,17a-methylenepregna-3,5-dien-20-one (0.5 g.), 5% palladium on charcoal (0.15 g.), cyclohexene (1 ml.) and ethanol (10 ml.) was heated under reflux for 2 /2 hours. The product, isolated as in Example 4, crystallised from hexane as prisms, M.P. 126 to 128 C., identical with an authentic specimen.

Example 13 A mixture of l7a-acetoxy-6-formyl-3-methoxypregna- 3,5-dien-20-one (5 g.), 5% palladium on charcoal (1.5

g.), cyclohexene (5 ml.) and ethanol ml.) was heated under reflux for 3 hours. More cyclohexene (2 ml.) was added, and the mixture refluxed for a further 1 hour. After removal of the catalyst, the product was isolated with ether, and its solution in methanol (50 ml.) treated with 3 drops of concentrated hydrochloric acid. The mixture was refluxed for 10 minutes and the product precipitated by the addition of water. crystallisation fromaqueous methanol gave 17a-acetoxy-6a-methyl proture with an authentic specimen.

gesterone, M.P. 206 to 208 C., not depressed in admix- Example 14 A mixture of 17,8-hydroxy-6-hydroxymethy1-17a-methyl-3-methoxyandrosta-3,5-diene (1 g.), 5% palladium on charcoal (0.25 g.), cyclohexene (5 ml.), acetic acid (5 ml.) and ethanol (25 ml.) was heated under reflux for 3 hours. The product, isolated as in Example 1, was purified from aqueous methanol. It had M.P. 134 to 135 C., and was identical 'v n'th authentic 6oz,17ocdimethyltesterone.

Example 15 A mixture. of 17a-acetoxy-6-formyl-16a-methyl-3-methoxypregna-3,5-dien-20-one (0.5g), 5% palladium on charcoal (0.15 g.), cyclohexene (1 ml.) and ethanol (20 2 ml.) was heated under reflux for 3 hours. The product, isolated as in Example 4, was purified from aqueous ethanol to give l7a-acetoxy-6a,16a-dimethylpregn-4-ene-3, 20-dione, M.P. 164 to 165 C., identical With an authentic specimen.

Example 16 A mixture of 21-acetoxy-115,17a-dihydroxy-6-hydroxymethyl-3-methoxypregna-3,S-dien-ZO-one (0.5 g.), ethanol (20 ml.),-acetic acid (10 ml.), cyclohexene (5 ml.) and 5% palladium on barium sulphate (0.5 g.) was-stirred and heated under reflux for 3 hours. The product, isolated as in Example 1, was purified from methanol. It had M.P. 208 to 211 C., and was identical with authentic 6a-methyl hydrocortisone acetate.

Example 17 A mixture of 17OL-3lCStOXy 21 fluoro-6-formyl-3-methoxypregna-Ii,5-dien-20-one (1 g.), ethanol (25 ml.), acetic acid (10 ml.), cyclohexene (5 m1.) and 5% palladium on charcoal (0.5 g.) was heated under reflux for 2 hours. The product, isolated as in Example 4, was crystallised from acetone/ hexane to give 17OL-aC6tOXy-21-flllOl'O-60tmethyl progesterone, M.P. 198 to 200 C., identical with an authentic specimen.

Example 18 A mixture of 21-acetoxy-3-ethoxy-6 formyl 17cc -hydroxypregna 3,5-dien-20-one (0.5 g.), ethanol (20 ml.),

acetic acid (5 ml.), cyclohexene (5 ml.) and 5% palladium on barium sulphate (0.5 g.) was heated under reflux'for 3 hours. The product, isolated ,as in Example l, was purified from methanol. It had M1. 195 to 196 C., and was identical with authentic 2l-acetoxy- 17a-hydroxy-6a-methyl progesterone.

We claim:

1. A process for the preparation of a compound selected from the group consisting of 3-oxo-A -6-methyl steroid compounds of the androstane, l9-norandrostane, 9/3,l0a-androstane, pregnane, l9-norpregnane, 913,100- pregnane, cholestane, stigmastane, ergostane and spirostane series comprising treating a 6-substituted steroidal- 3,5-diene of said series having in Rings A and B of the steroid nucleus the structure dun where Z represents the remainder of the steroid molecule, R is selected from the group consisting of O-alkyl, O-hydroxyalkyl, O-cycloalkyl and O-alkaryl and R is selected from the group consisting of with an acidified metallic catalyst selected from the palladium and platinum group of metals in the presence of at least one equivalent with respect to the steroid of an 2. A process as claimed in claim 1 wherein the acidifiedmetallic catalyst is palladium charcoal acidified with acetic acid.

3. A process as claimed in claim 1 wherein the metallic catalyst is palladium/barium sulphate acidified with acetic acid.

4. A process as claimed in claim 1 wherein the hydrogen donor is cyclohexene.

5. A process as claimed in claim 1 wherein the hydrogen donor is benzyl alcohol.

6. A process as claimed in claim 1 wherein the organic solvent is ethanol.

7. A process as claimed in claim 1 wherein the 6-substituted steroidal-3,5-diene in 10 to 20 vols. of ethanol is added to 0.2 to 1 part palladium charcoal and 1 to 5 parts cyclohexene and the mixture heated under reflux for 1 to 3 hours.

8.A process for the preparation of a compound selected from the group consisting of 3-oxo-A -6-methyl steroid compounds of the androstane, l9-norandrostane, 9,9,l0a-androstane, pregnane, 19-norpregnane, 9 3,100:- pregnane, cholestane, stigmastane, ergostane and spirostane series comprising treating a corresponding 3-enol ether substituted at C-6 with a member selected from the group consisting of formyl, hydroxymethyl, and acyloxymethyl with an acidified metallic catalyst selected from the palladium and platinum groups of metals in the presence of at least one equivalent with respect to the steroid of an unsaturated hydrocarbon hydrogen donor in a hydroxylic organic solvent.

No references cited. 

1. A PROCESS FOR THE PREPARATION OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-OXO-$4-6-METHYL STEROID COMPOUNDS OF THE ANDROSTANE, 19-NORANDROSTANE, 9B, 10A-ANDROSTANE, PREGNANE, 19 - NORPREGNANE, 9B, 10APREGNANE, CHOLESTANE, STIGMASTANE, ERGOSTANE AND SPIROSTANE SERIES COMPRISING TREATING A 6-SUBSTITUTED STEROIDAL3,5-DIENE OF SAID SERIES HAVING IN RINGS A AND B OF THE STEROID NUCLEUS THE STRUCTURE 